@article{FehrholzBersaniKrameretal.2012,
  author    = {Fehrholz, Markus and Bersani, Iliana and Kramer, Boris W. and Speer, Christian P. and Kunzmann, Steffen},
  title     = {Synergistic Effect of Caffeine and Glucocorticoids on Expression of Surfactant Protein B (SP-B) mRNA},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-77927},
  year      = {2012},
  abstract  = {Administration of glucocorticoids and caffeine is a common therapeutic intervention in the neonatal period, but possible interactions between these substances are still unclear. The present study investigated the effect of caffeine and different glucocorticoids on expression of surfactant protein (SP)-B, crucial for the physiological function of pulmonary surfactant. We measured expression levels of SP-B, various SP-B transcription factors including erythroblastic leukemia viral oncogene homolog 4 (ErbB4) and thyroid transcription factor-1 (TTF-1), as well as the glucocorticoid receptor (GR) after administering different doses of glucocorticoids, caffeine, cAMP, or the phosphodiesterase-4 inhibitor rolipram in the human airway epithelial cell line NCI-H441. Administration of dexamethasone (1 mM) or caffeine (5 mM) stimulated SP-B mRNA expression with a maximal of 38.8611.1-fold and 5.261.4-fold increase, respectively. Synergistic induction was achieved after coadministration of dexamethasone (1 mM) in combination with caffeine (10 mM) (206659.7-fold increase, p,0.0001) or cAMP (1 mM) (2136111-fold increase, p = 0.0108). SP-B mRNA was synergistically induced also by administration of caffeine with hydrocortisone (87.9639.0), prednisolone (154666.8), and betamethasone (12366.4). Rolipram also induced SP-B mRNA (64.9621.0-fold increase). We detected a higher expression of ErbB4 and GR mRNA (7.0- and 1.7-fold increase, respectively), whereas TTF-1, Jun B, c-Jun, SP1, SP3, and HNF-3a mRNA expression was predominantly unchanged. In accordance with mRNA data, mature SP-B was induced significantly by dexamethasone with caffeine (13.869.0-fold increase, p = 0.0134). We found a synergistic upregulation of SP-B mRNA expression induced by co-administration of various glucocorticoids and caffeine, achieved by accumulation of intracellular cAMP. This effect was mediated by a caffeinedependent phosphodiesterase inhibition and by upregulation of both ErbB4 and the GR. These results suggested that caffeine is able to induce the expression of SP-transcription factors and affects the signaling pathways of glucocorticoids, amplifying their effects. Co-administration of caffeine and corticosteroids may therefore be of benefit in surfactant homeostasis.},
  subject      = {Medizin},
  language  = {en}
}
@article{LaugFehrholzSchuetzeetal.2012,
  author    = {Laug, Roderich and Fehrholz, Markus and Sch{\"u}tze, Norbert and Kramer, Boris W. and Krump-Konvalinkova, Vera and Speer, Christian P. and Kunzmann, Steffen},
  title     = {IFN-gamma and TNF-alpha synergize to inhibit CTGF expression in human lung endothelial cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76253},
  year      = {2012},
  abstract  = {Connective tissue growth factor (CTGF/CCN2) is an angiogenetic and profibrotic factor, acting downstream of TGF-b, involved in both airway- and vascular remodeling. While the T-helper 1 (Th1) cytokine interferon-gamma (IFN-c) is well characterized as immune-modulatory and anti-fibrotic cytokine, the role of IFN-c in lung endothelial cells (LEC) is less defined. Tumour necrosis factor alpha (TNF-a) is another mediator that drives vascular remodeling in inflammation by influencing CTGF expression. In the present study we investigated the influence of IFN-c and TNF-a on CTGF expression in human LEC (HPMEC-ST1.6R) and the effect of CTGF knock down on human LEC. IFN-c and TNF-a down-regulated CTGF in human LEC at the promoter-, transcriptional- and translational-level in a dose- and time-dependent manner. The inhibitory effect of IFN-c on CTGF-expression could be almost completely compensated by the Jak inhibitor AG-490, showing the involvement of the Jak-Stat signaling pathway. Besides the inhibitory effect of IFN-c and TNF-a alone on CTGF expression and LEC proliferation, these cytokines had an additive inhibitory effect on proliferation as well as on CTGF expression when administered together. To study the functional role of CTGF in LEC, endogenous CTGF expression was down-regulated by a lentiviral system. CTGF silencing in LEC by transduction of CTGF shRNA reduced cell proliferation, but did not influence the anti-proliferative effect of IFN-c and TNF-a. In conclusion, our data demonstrated that CTGF was negatively regulated by IFN-c in LEC in a Jak/Stat signaling pathway-dependent manner. In addition, an additive effect of IFN-c and TNF-a on inhibition of CTGF expression and cell proliferation could be found. The inverse correlation between IFN-c and CTGF expression in LEC could mean that screwing the Th2 response to a Th1 response with an additional IFN-c production might be beneficial to avoid airway remodeling in asthma.},
  subject      = {Medizin},
  language  = {en}
}